Peroxisome Proliferator-activated Receptor Agonists Inhibit Inflammatory Edema and Hyperalgesia

Overview

Journal Inflammation

Specialties Allergy & Immunology
Pathology

Date 2002 Jun 27

PMID 12083418

Citations 24

Authors

Bradley K Taylor

Niren Dadia

Carolyn B Yang

Sendhil Krishnan

Mostafa Badr

Affiliations

Soon will be listed here.

Abstract

Previous studies have produced conflicting data on the contribution of the peroxisome proliferator-activated receptors (PPARs) to the inflammatory process. This study investigated the effects of several PPARalpha and PPARgamma subtype-specific agonists on the inflammation and hyperalgesia produced by intraplantar carrageenan injection in unanesthetized male Sprague-Dawley rats. Intraperitoneal administration of PPARalpha agonists reduced edema in parallel to their potencies determined in vitro. Perfluorooctanoic acid (PFOA) inhibited carrageenan-induced edema in a dose-dependent manner, and also reduced thermal hypersensitivity. Furthermore, PFOA produced much more robust effects when administered 0.5-24 hrs before carrageenan, as compared to when it was administered 1.5 hrs after carrageenan. Intraperitoneal administration of similar doses of the PPARgamma agonist rosiglitazone, but not the less potent agonist, troglitazone, reduced edema when administered before but not after carrageenan. We conclude that systemic administration of potent PPARalpha and PPARgamma agonists exert anti-hyperalgesic and/or antiinflammatory actions in vivo, possibly by interfering with the initiation of inflammation.

Citing Articles

Antinociceptive Effects of Cannabichromene (CBC) in Mice: Insights from von Frey, Tail-Flick, Formalin, and Acetone Tests.

Raup-Konsavage W, Sepulveda D, Wang J, Dokholyan N, Vrana K, Graziane N Biomedicines. 2024; 12(1).

PMID: 38255191 PMC: 10813533. DOI: 10.3390/biomedicines12010083.

Effects of Intra-BLA Administration of PPAR Antagonists on Formalin-Evoked Nociceptive Behaviour, Fear-Conditioned Analgesia, and Conditioned Fear in the Presence or Absence of Nociceptive Tone in Rats.

Gaspar J, Okine B, Dinneen D, Roche M, Finn D Molecules. 2022; 27(6).

PMID: 35335382 PMC: 8949000. DOI: 10.3390/molecules27062021.

The Role of PPAR Alpha in the Modulation of Innate Immunity.

Grabacka M, Pierzchalska M, Plonka P, Pierzchalski P Int J Mol Sci. 2021; 22(19).

PMID: 34638886 PMC: 8508635. DOI: 10.3390/ijms221910545.

Zerumbone Ameliorates Neuropathic Pain Symptoms via Cannabinoid and PPAR Receptors Using In Vivo and In Silico Models.

Chia J, Farouk A, Tengku Mohamad T, Sulaiman M, Zakaria H, Izzaty Hassan N Molecules. 2021; 26(13).

PMID: 34202590 PMC: 8270339. DOI: 10.3390/molecules26133849.

Thiazolidine Derivatives Attenuate Carrageenan-Induced Inflammatory Pain in Mice.

Malik Z, Abbas M, Al Kury L, Shah F, Alam M, Khan A Drug Des Devel Ther. 2021; 15:369-384.

PMID: 33574656 PMC: 7871178. DOI: 10.2147/DDDT.S281559.

References

Willson T, Brown P, Sternbach D, Henke B . The PPARs: from orphan receptors to drug discovery. J Med Chem. 2000; 43(4):527-50. DOI: 10.1021/jm990554g. View

Hill M, Clarke S, Rodgers K, Thornhill B, Peters J, Gonzalez F . Effect of peroxisome proliferator-activated receptor alpha activators on tumor necrosis factor expression in mice during endotoxemia. Infect Immun. 1999; 67(7):3488-93. PMC: 116535. DOI: 10.1128/IAI.67.7.3488-3493.1999. View

Albro P, Thomas R, Fishbein L . Metabolism of diethylhexyl phthalate by rats. Isolation and characterization of the urinary metabolites. J Chromatogr. 1973; 76(2):321-30. DOI: 10.1016/s0021-9673(01)96915-8. View

Spiegelman B . PPARgamma in monocytes: less pain, any gain?. Cell. 1998; 93(2):153-5. DOI: 10.1016/s0092-8674(00)81567-6. View

Youssef J, Badr M . Biology of senescent liver peroxisomes: role in hepatocellular aging and disease. Environ Health Perspect. 1999; 107(10):791-7. PMC: 1566613. DOI: 10.1289/ehp.99107791. View

Devchand P, Keller H, Peters J, Vazquez M, Gonzalez F, Wahli W . The PPARalpha-leukotriene B4 pathway to inflammation control. Nature. 1996; 384(6604):39-43. DOI: 10.1038/384039a0. View

Bentley P, Calder I, Elcombe C, Grasso P, Stringer D, Wiegand H . Hepatic peroxisome proliferation in rodents and its significance for humans. Food Chem Toxicol. 1993; 31(11):857-907. DOI: 10.1016/0278-6915(93)90225-n. View

Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans R . PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med. 2001; 7(1):48-52. DOI: 10.1038/83336. View

Henke B, Blanchard S, Brackeen M, Brown K, Cobb J, Collins J . N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J Med Chem. 1998; 41(25):5020-36. DOI: 10.1021/jm9804127. View

10.

Thieringer R, Fenyk-Melody J, Le Grand C, Shelton B, Detmers P, Somers E . Activation of peroxisome proliferator-activated receptor gamma does not inhibit IL-6 or TNF-alpha responses of macrophages to lipopolysaccharide in vitro or in vivo. J Immunol. 2000; 164(2):1046-54. DOI: 10.4049/jimmunol.164.2.1046. View

11.

Hattori Y, Hattori S, Kasai K . Troglitazone upregulates nitric oxide synthesis in vascular smooth muscle cells. Hypertension. 1999; 33(4):943-8. DOI: 10.1161/01.hyp.33.4.943. View

12.

Jiang C, Ting A, Seed B . PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998; 391(6662):82-6. DOI: 10.1038/34184. View

13.

Youssef J, Badr M . Extraperoxisomal targets of peroxisome proliferators: mitochondrial, microsomal, and cytosolic effects. Implications for health and disease. Crit Rev Toxicol. 1998; 28(1):1-33. DOI: 10.1080/10408449891344182. View

14.

Gelman L, Fruchart J, Auwerx J . An update on the mechanisms of action of the peroxisome proliferator-activated receptors (PPARs) and their roles in inflammation and cancer. Cell Mol Life Sci. 1999; 55(6-7):932-43. PMC: 11147039. DOI: 10.1007/s000180050345. View

15.

Petrova T, Akama K, Van Eldik L . Cyclopentenone prostaglandins suppress activation of microglia: down-regulation of inducible nitric-oxide synthase by 15-deoxy-Delta12,14-prostaglandin J2. Proc Natl Acad Sci U S A. 1999; 96(8):4668-73. PMC: 16390. DOI: 10.1073/pnas.96.8.4668. View

16.

Maloney E, Waxman D . trans-Activation of PPARalpha and PPARgamma by structurally diverse environmental chemicals. Toxicol Appl Pharmacol. 1999; 161(2):209-18. DOI: 10.1006/taap.1999.8809. View

17.

Chinetti G, Fruchart J, Staels B . Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res. 2000; 49(10):497-505. DOI: 10.1007/s000110050622. View

18.

Ricote M, Li A, Willson T, Kelly C, Glass C . The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998; 391(6662):79-82. DOI: 10.1038/34178. View

19.

Hargreaves K, Dubner R, Brown F, Flores C, Joris J . A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988; 32(1):77-88. DOI: 10.1016/0304-3959(88)90026-7. View

20.

Ricote M, Huang J, Welch J, Glass C . The peroxisome proliferator-activated receptor(PPARgamma) as a regulator of monocyte/macrophage function. J Leukoc Biol. 1999; 66(5):733-9. DOI: 10.1002/jlb.66.5.733. View